A stereoselective approach for the total synthesis of (5R,7R,9R)-7,9-dihydroxy-5-decanolide#

A stereoselective approach for the total synthesis of lactone (5R,7R,9R)-7,9-dihydroxy-5-decanolide is described. The sequence of synthetic reactions involves a Keck asymmetric allylation, diastereoselective iodo-carbonate cyclization, regioselective ring-opening reaction, oxidative lactonization.     

SnCl2-mediated carbonyl allylation in fully aqueous media

Systematic studies were performed on SnCl₂-mediated carbonyl allylation reaction between aldehydes and allyl halides in fully aqueous media. Totally three valuable reaction systems were discovered, which were SnCl₂/CuCl₂, SnCl₂/TiCl₃, and SnCl₂/PdCl₂. They all provided good to excellent yields in the allylation of aliphatic and aromatic aldehydes under very mild and convenient conditions. SnCl₂, by itself, was also found to be effective for the allylation reaction when allyl bromide was employed. However, the SnCl₂-only reaction could only tolerate very small amount of water as the solvent. The SnCl₂/CuCl₂, SnCl₂/TiCl₃, and SnCl₂/PdCl₂-mediated reactions exhibited good regioselectivity favoring the γ-adduct when cinnamyl halides were employed as the allylation reagent. The same reactions with cinnamyl halides also showed good diastereoselectivity favoring the anti-product. Mechanistic studies using proton NMR techniques suggested that the additive (i.e., CuCl₂, TiCl₃, PdCl₂) could accelerate the formation of allyltin intermediate, but this step was shown not to be the most important for the allylation. Thus we proposed that the Lewis acid catalysis effect exerted by the additive was the main reason for the observed reactivity enhancement.     

Resolution of (R,S)-flurbiprofen catalysed by dry mycelia in organic solvent

Mycelia of Aspergillus oryzae display high enantioselectivity towards (R)-flurbiprofen and can be efficiently used in pure organic solvent for the resolution of (R,S)-flurbiprofen through esterification. The use of the lyophilized mycelia facilitates the separation process so that in one step the two enantiomers of flurbiprofen, which are both valuable for pharmaceutical applications, can be easily separated. The biotransformation can be carried out in different apolar solvents using different primary alcohols as nucleophiles under very mild conditions.     

Deoxyfluorination of alcohols using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine

Deoxyfluorination of alcohols was carried out using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine (DFMBA). Primary alcohols were effectively converted to fluorides under microwave irradiation or conventional heating. Deoxyfluorination of an anomeric hydroxy group in sugars by DFMBA proceeded at below room temperature and glycosyl fluorides could be obtained in good yields. The deoxyfluorination reaction chemoselectively proceeded and various protecting groups on the sugar can survive under the reaction conditions.     

Microwave-assisted synthesis of methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-2-carboxylate through unexpected stereoselective substitution reaction

Methyl (1S,2R,4S,5R)-7-aza-5-bromo-bicyclo[2.2.1]heptane-2-carboxylate was synthesized in high yield in short time from methyl (1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanecarboxylate through intramolecular cycloamination under microwave-assisted conditions. The following substitution reaction by trifluoro-acetate anion also took place in microwave-assisted conditions to afford methyl (1S,2R,4S,5S)-7-aza-5-hydroxy-bicyclo[2.2.1]heptane-2-carboxylate. In the acyloxylation reaction, unusual endo-selectivity was observed owing to 7-azabicyclo[2.2.1]heptane skeleton.     

Indium- and zinc-mediated Barbier-type allylations of an N,N-(dimethylsulfamoyl)-protected aldimine and subsequent deprotection

Barbier-type Zn and In-mediated allylations of an N,N-(dimethylsulfamoyl)-protected aldimine with different allyl bromides were investigated for the preparation of N-homoallylic sulfamides. The desired N,N-(dimethylsulfamoyl)-protected products were obtained in moderate to high yields in THF as the optimal solvent. Their further derivatization was demonstrated by a facile preparation of a functionalized dehydropiperidine by an allylation/olefin metathesis reaction sequence. A high yielding deprotection of the N,N-dimethylsulfamoyl group was likewise demonstrated.     

Three-component sequential synthesis of N,N′-disubstituted 5-arylidenedihydropyrimidine-2,4-dione

A three-component sequential process consisting in (1) in situ formation of carbodiimides by Staudinger reaction, (2) reaction with 2-(bromomethyl)-3-aryl-2-propenoic acids, and (3) final cyclization of the resulting N-acylurea intermediates in order to obtain the synthesis of an array of N,N′-disubstituted 5-arylidenedihydropyrimidine-2,4-dione under mild conditions is presented.     

A new approach to construction of isoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAF reaction

The interaction between 1-furyl-1,2,3,4-tetrahydroisoquinolines and unsaturated acids derivatives (acryloyl, methacryloyl, and crotonoyl chloride, maleic and citraconic anhydride) was studied. It was shown that the reaction proceeds via amide formation and subsequent intramolecular Diels-Alder reaction of the furan (IMDAF). The [4+2] cycloaddition proceeded under mild reaction conditions (25-80 °C) and afforded only the exo-adduct in a high yield. With this method, a new approach to the isoindolo[1,2-a]isoquinoline system, the basic structural element of alkaloids Jamtine, Hirsutine, and Nuevamine, is proposed.     

Convenient synthesis and unusual reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes

The reaction of 4-oxo-4H-chromen-3-carbaldehydes with coumarin-4-acetic acids under the Perkin conditions follows an interesting pathway that involves aldol reaction and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton. In contrast to chromone-3-carbaldehydes, the same reaction with chromone-2-carbaldehydes yielded only the aldol condensation product. The reaction was performed under thermal and microwave conditions. The reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes in water, alcohol and acetic acid was described.     

P′CP′-Pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines

The P′CP′-pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines with allyl(tributyl)stannane is investigated for the preparation of N-homoallylic sulfamides. The desired N,N-dimethylsulfamoyl-protected products are obtained in moderate to high yields in DMF under very mild conditions and a high yielding and convenient deprotection of the N,N-dimethylsulfamoyl group is also demonstrated.     

An easy route to atropoisomeric bipyridine N,N′-dioxides and allylation of aldehydes

Axially chiral bipyridine N,N′-dioxides (Lewis basic organocatalysts) are easily accessible in three steps from commercially available material. The key step of this reaction sequence is cobalt-catalyzed heterocyclotrimerization of 1-pyridyl-1,7-octadiynes with nitriles. Our effort was focused on the synthesis of unsymmetrically substituted bipyridines. The scope of the cyclotrimerization reaction was tested under thermal and microwave conditions. Two of the synthesized bipyridine N,N′-dioxides were successfully resolved into enantiomers and tested in enantioselective allylation of aldehydes.     

Selective synthesis of fluorinated carbohydrates using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine

Deoxyfluorination of a hydroxy group in carbohydrates was carried out using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine. A primary hydroxy group in carbohydrates was effectively converted to the corresponding fluoride under microwave irradiation or at 100 °C. Deoxyfluorination of hydroxy groups at the anomeric position proceeded at below room temperature, and glycosyl fluorides could be obtained in good yields. The reaction chemoselectively proceeded, and various protecting groups of carbohydrates can survive under the reaction conditions.     

Domino pericyclic reactions of acyclic conjugated (E,Z,E,E)-tetraenes

Acyclic conjugated (E,Z,E,E)-tetraenes, upon thermolysis, undergo a domino pericyclic process involving 6π electrocyclisation of the (E,Z,E)-triene moiety to give the corresponding cis-disubstituted 5-vinyl-1,3-cyclohexadienes, followed by an intramolecular Diels-Alder reaction with the vinyl side chain to give tricyclo[3.2.1.0^2,7]oct-3-enes.     

Polydisuccinimides: Polyaddition reactions of aliphatic and aromatic diamines to N,N′-bismaleimide

Polyaddition reactions of aliphatic and aromatic diamines to N,N′-bismaleimide and model compounds have been investigated in order to establish some properties of this imide. Glacial acetic acid has a catalytic effect when used as solvent in the preparation of aspartimide compounds. Aromatic diamines show a much smaller reactivity than aliphatic, the former giving polydisuccinimides and the latter polyamides under the same reaction conditions. Addition reactions of N,N′-bismaleimide proceed either by an ionic mechanism in polar solvents or by a homolytic process in solvents precluding ion formation. The thermal stability and the infrared spectra of the new polymers are discussed.     

Lewis acid-promoted cascade reaction of primary amine, 2-butynedioate,and propargylic alcohol: a convenient approach to 1,2-dihydropyridines and 1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-diones

1,2-Dihydropyridine-5,6-dicarboxylates were efficiently constructed through a cascade reaction of primary amine, 2-butynedioate and propargylic alcohol in the presence of Lewis acid under mild conditions. As exceptional, 1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-diones were approached when the primary amine was methylamine. Possible mechanism for the formation of 1,2-dihydropyridine skeleton is proposed. The process involves 1,3,4-pentatrien-1-amine as a key intermediate that formed in situ by trapping allenic carbocations with enamines.     

Synthesis of N-acyl-N,O-acetals from N-aryl amides and acetals in the presence of TMSOTf

Secondary amides undergo in situ silyl imidate formation mediated by TMSOTf and an amine base, followed by addition to acetal acceptors to provide N-acyl-N,O-acetals in good yields. An analogous, high-yielding reaction is observed with 2-mercaptothiazoline as the silyl imidate precursor. Competing reduction of the acetal to the corresponding methyl ether via transfer hydrogenation can be circumvented by the replacement of CY₂NMe with 2,6-lutidine under otherwise identical reaction conditions.     

Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin

A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin from l-ascorbic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM deprotection and bicyclic ketal formation was carried under Pd/C, H₂ followed by acid treatment.     

Copper-catalyzed amination of aromatic halides with 2-N,N-dimethylaminoethanol as solvent

A copper-catalyzed amination of aromatic halides under mild conditions using N,N-dimethylaminoethanol as solvent is described. We have studied this reaction in some detail varying the copper source, base, water content and other parameters including the scope of useful amine and aromatic halide structures. A variety of 4-halo-N,N-cycloalkylanilines and 2-N,N-cycloalkylaminothiophenes were synthesized for further elaboration into chromophores for optoelectronic applications.     

Condensation of Vilsmeier salts,derived from tetraalkylureas,with amidoximes: a novel approach to access N,N-dialkyl-1,2,4-oxadiazol-5-amines

A novel approach, condensation of Vilsmeier salts and amidoximes, to access N,N-dialkyl-1,2,4-oxadiazol-5-amines has been developed. By this approach, a broad range of N,N-dialkyl-1,2,4-oxadiazol-5-amines, including aromatic, heteroaromatic, and aliphatic substituents, can be synthesized in good to high yields (up to 82%) under mild reaction conditions.     

Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.